p21-Activated Kinases 1 and 3 Control Brain Size through Coordinating Neuronal Complexity and Synaptic Properties
p21-Activated Kinases 1 and 3 Control Brain Size through Coordinating Neuronal Complexity and Synaptic Properties
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DOI：
10.1128/mcb.00969-10
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
Jia, Zhengping
中科院分区：
文献类型：
--
作者：
Huang, Wayne;Zhou, Zikai;Jia, Zhengping
协调出生后大脑扩大、突触特性和认知的分子机制仍然是一个谜。在这里，我们证明了由p21激活激酶（PAKs）控制的神经元复杂性是出生后大脑扩大和突触特性的关键决定因素。我们发现，缺乏PAK 1和PAK 3的双敲除（DK）小鼠出生时健康，大脑大小和结构正常，但出生后大脑生长严重受损，导致脑体积急剧减少。值得注意的是，由于细胞密度的显著增加，脑体积的减小伴随着总细胞计数的最小变化。然而，DK神经元具有较小的索马，明显简化的树突状的乔木/轴突，和突触密度降低。令人惊讶的是，由于增强的个体突触效能，DK小鼠具有升高的基础突触反应，但双向突触可塑性严重受损。PAK 1和PAK 3的作用可能是由cofilin依赖的肌动蛋白调节介导的，因为在DK小鼠中cofilin的活性和肌动蛋白丝的性质被改变。这些结果揭示了PAK 1和PAK 3在协调神经元复杂性和突触特性中的重要作用，并突出了树突/轴突生长在决定出生后大脑生长和达到正常大脑大小和功能中的至关重要性。
The molecular mechanisms that coordinate postnatal brain enlargement, synaptic properties, and cognition remain an enigma. Here, we demonstrate that neuronal complexity controlled by p21-activated kinases (PAKs) is a key determinant for postnatal brain enlargement and synaptic properties. We showed that double-knockout (DK) mice lacking both PAK1 and PAK3 were born healthy, with normal brain size and structure, but severely impaired in postnatal brain growth, resulting in a dramatic reduction in brain volume. Remarkably, the reduced brain size was accompanied by minimal changes in total cell count, due to a significant increase in cell density. However, the DK neurons have smaller soma, markedly simplified dendritic arbors/axons, and reduced synapse density. Surprisingly, the DK mice had elevated basal synaptic responses due to enhanced individual synaptic potency but were severely impaired in bidirectional synaptic plasticity. The actions of PAK1 and PAK3 are possibly mediated by cofilin-dependent actin regulation, because the activity of cofilin and the properties of actin filaments were altered in the DK mice. These results reveal an essential in vivo role of PAK1 and PAK3 in coordinating neuronal complexity and synaptic properties and highlight the critical importance of dendrite/axon growth in dictating postnatal brain growth and attainment of normal brain size and function.